The cerebral cortex is involved in higher-order cognitive processing, learning, and memory. These functions are mediated by excitatory projection neurons and inhibitory interneurons. Interneurons, which comprise approximately 20% of the cortical neurons (Krimer et al., “Prefrontal Microcircuits: Membrane Properties and Excitatory Input of Local, Medium, and Wide Arbor Interneurons,” J Neurosci 21(11):3788 (2001)), can be divided into subgroups based on neurochemical markers, connectivity, and physiological properties.
GABA(γ-aminobutyric acid)ergic interneurons play crucial roles in nearly all aspects of brain function. By providing the major source of inhibitory circuitry in the cerebral cortex, GABAergic interneurons are required for the synchronous activity necessary to generate sustained oscillations among neurons within a network that are essential during perception, coordinated movement, learning and memory. Cortical deficits in inhibitory neuronal transmission have been implicated in several neurological and psychiatric disorders including epilepsy, autism, and schizophrenia.
Previous studies have demonstrated that cortical interneuron precursors have an amazing ability to migrate, mature, and function after transplantation into adult cerebral cortex. Since these cells normally control cortical activity, it has been proposed to use them in a cell based therapy for chronic seizures of focal origin. Particularly in the case of intractable seizure disorders, cell-based therapy has been proposed as an alternative to surgical intervention. It is anticipated that such cells can also be used in cell-based therapy for forebrain disorders such as medication-intractable seizures and Parkinson's disease. Such therapy could be used either to harness the intrinsic ability of these cells to inhibit activity, or a drug delivery system after genetic manipulation to express therapeutic agents (i.e., agents that suppress seizures, including GABA, neuropeptide Y, adenosine). However, the practical use of interneuron precursors in preclinical or clinical studies requires the ability to generate very large numbers of these cells, which currently does not exist.
The present invention is directed to overcoming these and other deficiencies in the art.